Brucine-lactone compound



Patented Dec. 4, 1945 UNITED STATES PATENT OFFICE BRUCINE-LACTONECOMPOUND Max Tishler, Rahway, and Ralph H. Beutel,

Newark, N. J., Rahway, N. J

assignors to Merck & (30., Inc., a corporation of New Jersey No Drawing.Application November 27, 1943, Serial No. 512,056

Claims.

ma-butyrolactone or a chemical equivalent there- 01. In thiscondensation, if the dextro-rotatory form of the lactone is used, theproduct does not possess the desired physiological activity henceresolution of the racemic-lactone obtained by synthetic means isessential before condensation if satisfactory yields of the desiredproduct are to be obtained.

According to one aspect of the present invention, the racemic syntheticlactone is resolved into its stereisomers by reacting the racemiccompound per se with brucine alkaloid under conditions such that saltformation does notoccur. The laevorotatory lactone forms a complex withbrucine that can be isolated readily.

The complex can be represented by the formula:

In addition to this complex another type of brucine compound can beprepared, namely: brucinea -gamma-dihydroxyp 5 -dimethylbutyrate whichis formed by metathesis when an aqueous solution of bariuma-gamma-dihydroxyp-p-dimethyl-butyrate (derived from the laevo- Theproperties of these two compounds are con trashed in the followingtable.

Complex True salt (0:) (H0013) .-degrees.- 87.5 I 3. 25 Melting point.211-212 213-214.

For For eHmOaCzaHumNz 00H1204.C2:H2604N2 Caleu- Calculated Fmmd latedFmmd Elementary analysis:

G percent 66. 39 66. 52 64. 19 64. 14 H percent. 6. 92 6. 96 7.06 6. 68N .percent 5. 34 5. 51 5.16 4. 98

Solubility Hot ethanol (95 o Water Ethyl acetate pH (aq. soln.) Molsbrucine per mol 1 of compound.

The reaction between brucine base and the l-lactone to produce thecomplex occurs most easily in a solvent capable of dissolvingthereactants. It is desirable, however, that the solvent be selected sothat the reaction product is but slightly soluble, or relativelyslightly soluble, therein, thus causing separation of the complex.Ethanol is satisfactor for this purpose, either in anhydrous or usualcommercial (95%) state. If desired, however, the complex can be formedin other solvents, for instance, water, ethyl acetate,

dioxane and chloroform. When water is used,

the reaction mixture is agitated during reaction to assure continuedsuspension of particles of the but slightly soluble brucine. Whenchloroform is used, the complex can be readily precipitated by additionof a solvent such as ethe The following examples illustrate methods ofrotatory lactone) is mixed with brucine sulfate. carrying out thepresent invention, but it is to be understood that these examples aregiven by way of illustration and not of limitation.

Example 1 About 48.8 g. of brucine base are dissolved in approximately93 cc. of ethanol (95%) at somewhat above room temperature, say about 500., and approximately 46.6 g. of racemic a-hydroxy.p-p-dimethyl-gamma-butyrolactone (dissolved in acetone to give asolution of about 50% by wei ht concentration) are added. The solutionis cooled for about one and a half hours, and the crystalline materialwhich is formed is removed from the supernatant liquid, washed withethanol 95%) and dried in vacuo at about C. for approximately two hours.The product is the purified brucine-l-lactone complex.

The l-lactone is obtained from the brucinel-lactone complex by treatmentwith a base such as aqueous sodium hydroxide, extraction withchloroform, ethylene dichloride or the like to remove the alkaloid. Theaqueous solution is then acidified, heated, cooled and the lactoneextracted with ether or benzene. The extract is washed with dilute acidand evaporated to recover the lactone.

Alternatively, the l-lactone is obtained from the complex by treatmentwith an acid such as hydrochloric, sulfuric, phosphoric and the like,and extraction with ether, benzene or the like to remove the lactone.The extract is washed with dilute acid and evaporated to recover thelactone.

Example 2 Example 3 About 23.3 g. of brucine base are dissolved inapproximately 233 cc. of hot ethyl acetate. and

asoaaer about 13 g. of racemic a-hydroxy-p-p-dimethylgamma-butyrolactoneare added. After cooling Example '4 The procedure and proportions ofreactants set forth in Example 3 are used but an equal volume of dioxaneis substituted for the ethyl acetate there used. The product is isolatedas in the said example. Chloroform can also be substi tuted in theprocedure for the ethyl acetate and the complex precipitated by theaddition of ether.

Modifications may be made in carrying out the present invention withoutdeparting from the spirit and scope thereof and the invention is to belimited only by the appended claims.

What is claimed is:

'1. The process that includes the step comprising reacting racemica-hydroxy-p-fl-dimethylgamma-butyrolactone with brucine in anessentially inert, neutral liquid solvent and removing thebrucine-l-lactone complex formed.

2. The process that includes the step comprising reacting racemicu-hydroxy-p-B-dimethylgamma-butyrolactone with brucine in alcohol 5. Abrucine-l a hydroXy B B dimethylgamma-butyrolactone complex melting atabout 210 0., and having the optical rotation of about [u] =87 whenmeasured in 2% chloroform solution.

MAX TISHLER. RALPH H. BEUTEL.

of matter represented by the

